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1.
Toxicol Lett ; 322: 98-103, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954869

RESUMO

Patients intoxicated with organophosphorous compounds may need general anaesthesia to enable mechanical ventilation or for control of epileptiform seizures. It is well known that cholinergic overstimulation attenuates the efficacy of general anaesthetics to reduce spontaneous network activity in the cortex. However, it is not clear how propofol, the most frequently used intravenous anaesthetic today, is affected. Here, we investigated the effects of cholinergic overstimulation induced by soman and acetylcholine on the ability of propofol to depress spontaneous action potential activity in organotypic cortical slices measured by extracellular voltage recordings. Cholinergic overstimulation by co-application of soman and acetylcholine (10 µM each) did not reduce the relative inhibition of propofol (1.0 µM; mean normalized action potential firing rate 0.49 ± 0.06 of control condition, p < 0.001, Wilcoxon signed rank test) but clearly reduced its efficacy. Co-application of atropine (10 nM) did not improve the efficacy. Propofol preserved its relative inhibitory potential but did not produce a degree of neuronal depression which can be expected to assure hypnosis in humans. Since a combination with atropine did not improve its efficacy, an increase in dosage will probably be necessary when propofol is used in victims suffering from organophosphorous intoxication.


Assuntos
Acetilcolina/toxicidade , Potenciais de Ação/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Rede Nervosa/efeitos dos fármacos , Propofol/farmacologia , Soman/toxicidade , Acetilcolina/administração & dosagem , Anestesia Geral , Anestésicos Intravenosos/administração & dosagem , Animais , Camundongos Endogâmicos C57BL , Neocórtex/efeitos dos fármacos , Neocórtex/fisiologia , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Intoxicação por Organofosfatos , Propofol/administração & dosagem , Soman/administração & dosagem
2.
Biol Aujourdhui ; 213(3-4): 141-145, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829934

RESUMO

Addiction is a chronic disease that has serious consequences, both in terms of public health and economy. Clear characteristics distinguish recreational and controlled use from addiction. Thus, today, addiction includes the notions of compulsive drug use, associated with a loss of control over consumption, leading to craving. When consumption is stopped, withdrawal symptoms may emerge: a negative emotional state, cognitive problems and physical symptoms with some products (alcohol and opiates, for example). Relapse episodes may occur during this withdrawal period, countering the negative effects of withdrawal. Relapse episodes can also be observed after long periods of abstinence. They can be precipitated by re-exposure to the context in which the drugs were taken, or by stress. Regardless of the stage of addiction (e.g., development of the addictive behavior, or relapse) changes in brain function and structure can be observed. Some brain structures are therefore modified, such as the prefrontal cortex, where several neuroadaptations have been identified. Some of these changes are described in this paper.


Assuntos
Cocaína/farmacologia , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Psicotrópicos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/fisiopatologia , Comportamento Aditivo/psicologia , Transtornos Relacionados ao Uso de Cocaína/etiologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Humanos , Rede Nervosa/fisiologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia , Síndrome de Abstinência a Substâncias/psicologia
3.
Handb Clin Neurol ; 165: 83-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727232

RESUMO

Parkinson disease (PD) is a neurodegenerative disorder with a complex pathophysiology characterized by the progressive loss of dopaminergic neurons within the substantia nigra. Persons with PD experience several motoric and neuropsychiatric symptoms. Neuropsychiatric features of PD include depression, anxiety, psychosis, impulse control disorders, and apathy. In this chapter, we will utilize the National Institutes of Mental Health Research Domain Criteria (RDoC) to frame and integrate observations from two prevailing disease constructions: neurotransmitter anomalies and circuit physiology. When there is available evidence, we posit how unified translational observations may have clinical relevance and postulate importance outside of PD. Finally, we review the limited evidence available for pharmacologic management of these symptoms.


Assuntos
Encéfalo/fisiopatologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Rede Nervosa/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/uso terapêutico , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Encéfalo/efeitos dos fármacos , Humanos , Transtornos Mentais/psicologia , Rede Nervosa/efeitos dos fármacos , Doença de Parkinson/psicologia , Psicofarmacologia
4.
Elife ; 82019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713514

RESUMO

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.


Assuntos
Calbindina 2/genética , Interneurônios/metabolismo , Neuralgia/fisiopatologia , Neurônios/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Analgésicos Opioides/farmacologia , Animais , Calbindina 2/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Halorrodopsinas/genética , Halorrodopsinas/metabolismo , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Camundongos , Camundongos Transgênicos , Morfina/farmacologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neuralgia/tratamento farmacológico , Neuralgia/genética , Neuralgia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Optogenética/métodos , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Estimulação Luminosa , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/patologia , Técnicas de Cultura de Tecidos , Transgenes
5.
Anesthesiology ; 131(6): 1239-1253, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31567366

RESUMO

BACKGROUND: Functional brain connectivity studies can provide important information about changes in brain-state dynamics during general anesthesia. In adults, γ-aminobutyric acid-mediated agents disrupt integration of information from local to the whole-brain scale. Beginning around 3 to 4 months postnatal age, γ-aminobutyric acid-mediated anesthetics such as sevoflurane generate α-electroencephalography oscillations. In previous studies of sevoflurane-anesthetized infants 0 to 3.9 months of age, α-oscillations were absent, and power spectra did not distinguish between anesthetized and emergence from anesthesia conditions. Few studies detailing functional connectivity during general anesthesia in infants exist. This study's aim was to identify changes in functional connectivity of the infant brain during anesthesia. METHODS: A retrospective cohort study was performed using multichannel electroencephalograph recordings of 20 infants aged 0 to 3.9 months old who underwent sevoflurane anesthesia for elective surgery. Whole-brain functional connectivity was evaluated during maintenance of a surgical state of anesthesia and during emergence from anesthesia. Functional connectivity was represented as networks, and network efficiency indices (including complexity and modularity) were computed at the sensor and source levels. RESULTS: Sevoflurane decreased functional connectivity at the δ-frequency (1 to 4 Hz) in infants 0 to 3.9 months old when comparing anesthesia with emergence. At the sensor level, complexity decreased during anesthesia, showing less whole-brain integration with prominent alterations in the connectivity of frontal and parietal sensors (median difference, 0.0293; 95% CI, -0.0016 to 0.0397). At the source level, similar results were observed (median difference, 0.0201; 95% CI, -0.0025 to 0.0482) with prominent alterations in the connectivity between default-mode and frontoparietal regions. Anesthesia resulted in fragmented modules as modularity increased at the sensor (median difference, 0.0562; 95% CI, 0.0048 to 0.1298) and source (median difference, 0.0548; 95% CI, -0.0040 to 0.1074) levels. CONCLUSIONS: Sevoflurane is associated with decreased capacity for efficient information transfer in the infant brain. Such findings strengthen the hypothesis that conscious processing relies on an efficient system of integrated information transfer across the whole brain.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Encéfalo/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Ritmo Delta/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Sevoflurano/administração & dosagem , Encéfalo/fisiologia , Estudos de Coortes , Estado de Consciência/fisiologia , Ritmo Delta/fisiologia , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Rede Nervosa/fisiologia , Estudos Retrospectivos , Inconsciência/induzido quimicamente , Inconsciência/fisiopatologia
6.
PLoS One ; 14(9): e0222957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536584

RESUMO

The ventral midbrain supports a variety of functions through the heterogeneity of neurons. Dopaminergic and GABA neurons within this region are particularly susceptible targets of amphetamine-class psychostimulants such as methamphetamine. While this has been evidenced through single-neuron methods, it remains unclear whether and to what extent the local neuronal network is affected and if so, by which mechanisms. Both GABAergic and dopaminergic neurons were heavily featured within the primary ventral midbrain network model system. Using spontaneous calcium activity, our data suggest methamphetamine decreased total network output via a D2 receptor-dependent manner. Over culture duration, functional connectivity between neurons decreased significantly but was unaffected by methamphetamine. However, across culture duration, exposure to methamphetamine significantly altered changes in network assortativity. Here we have established primary ventral midbrain networks culture as a viable model system that reveals specific changes in network activity, connectivity, and topology modulation by methamphetamine. This network culture system enables control over the type and number of neurons that comprise a network and facilitates detection of emergent properties that arise from the specific organization. Thus, the multidimensional properties of methamphetamine can be unraveled, leading to a better understanding of its impact on the local network structure and function.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Metanfetamina/farmacologia , Rede Nervosa/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Células Cultivadas , Estimulantes do Sistema Nervoso Central/farmacologia , Neurônios Dopaminérgicos/fisiologia , Feminino , Neurônios GABAérgicos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neuroimagem/métodos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/fisiologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/fisiologia
7.
Psychiatry Res Neuroimaging ; 292: 23-31, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476712

RESUMO

Methamphetamine is a highly addictive psychostimulant. A subset of methamphetamine users develops methamphetamine-associated psychosis (MAP), which causes poorer prognoses and cognitive function than those with no psychosis (MNP). Comprehensive and integrative summaries of studies utilizing various neuroimaging modalities (structural, functional, and neurochemical) are limited. We conducted a systematic review of literature regarding clinical neuroimaging research published between January 1988 and July 2018 using the PubMed, Web of Science, Scopus, and ScienceDirect databases. Studies comparing the neuroimaging of patients with MAP with healthy controls or patients with MNP or schizophrenia were included to understand the distinct profiles associated with MAP. A total of six structural, three functional, and three neurochemical studies were reviewed. A general trend was identified that showed MAP-related brain alterations were mainly in the frontal lobe (especially the orbitofrontal cortex), striatum, and limbic systems (amygdala and hippocampus). Furthermore, some clinical manifestations, such as the severity of psychotic symptoms and cognitive performance, were correlated with neuroimaging abnormalities. In summary, distinct structural, functional, and neurochemical changes, especially in the frontostriatal circuit and network dynamic systems, play critical roles in the pathophysiology of MAP. Future studies using longitudinal study designs and including individuals with MNP and schizophrenia as controls are warranted.


Assuntos
Encéfalo/diagnóstico por imagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Rede Nervosa/diagnóstico por imagem , Neuroimagem/métodos , Psicoses Induzidas por Substâncias/diagnóstico por imagem , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/efeitos dos fármacos , Psicoses Induzidas por Substâncias/psicologia
8.
Neurología (Barc., Ed. impr.) ; 34(7): 461-468, sept. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-186348

RESUMO

Introducción: En los mamíferos, el complejo pre-Bötzinger (preBötC) es una red neuronal bilateral y simétrica localizada en el tallo cerebral, la cual es indispensable para la generación y modulación del ritmo respiratorio. En humanos existen pocos estudios acerca del preBötC y su relación con enfermedades neurológicas no ha sido descrita. Sin embargo, la importancia del preBötC en el control neural del ritmo respiratorio y su posible participación en enfermedades neurológicas en humanos ha sido mostrada gracias a la manipulación farmacológica y de lesiones del preBötC realizadas en modelos animales in vivo e in vitro. Método: En esta revisión describimos los efectos de algunos fármacos sobre la actividad inspiratoria in vitro en el modelo de rebanada transversal del tallo cerebral que contiene el preBötC, y algunos experimentos in vivo. La farmacología fue clasificada de acuerdo con los principales sistemas de neurotransmisión y con la importancia de los fármacos como estimuladores o inhibidores de la actividad del preBötC y, por tanto, de la generación del ritmo respiratorio. Conclusiones: El neurólogo clínico encontrará esta información relevante para entender cómo el sistema nervioso central genera el ritmo respiratorio y, además, podrá relacionarla con las observaciones hechas durante su práctica


Introduction: In mammals, the preBötzinger complex (preBötC) is a bilateral and symmetrical neural network located in the brainstem which is essential for the generation and modulation of respiratory rhythm. There are few human studies about the preBötC and, its relationship with neurological diseases has not been described. However, the importance of the preBötC in neural control of breathing and its potential participation in neurological diseases in humans, has been suggested based on pharmacological manipulation and lesion of the preBötC in animal models, both in vivo and in vitro. Method: In this review, we describe the effects of some drugs on the inspiratory activity in vitro in a transverse slice that contains the preBötC, as well as some in vivo experiments. Drugs were classified according to their effects on the main neurotransmitter systems and their importance as stimulators or inhibitors of preBötC activity and therefore for the generation of the respiratory rhythm. Conclusion: Clinical neurologists will find this information relevant to understanding how the central nervous system generates the respiratory rhythm and may also relate this information to the findings made in daily practice


Assuntos
Humanos , Animais , Tronco Encefálico/fisiologia , Rede Nervosa/fisiologia , Respiração/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos
9.
Nat Nanotechnol ; 14(10): 967-973, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427746

RESUMO

Connecting neural circuit output to behaviour can be facilitated by the precise chemical manipulation of specific cell populations1,2. Engineered receptors exclusively activated by designer small molecules enable manipulation of specific neural pathways3,4. However, their application to studies of behaviour has thus far been hampered by a trade-off between the low temporal resolution of systemic injection versus the invasiveness of implanted cannulae or infusion pumps2. Here, we developed a remotely controlled chemomagnetic modulation-a nanomaterials-based technique that permits the pharmacological interrogation of targeted neural populations in freely moving subjects. The heat dissipated by magnetic nanoparticles (MNPs) in the presence of alternating magnetic fields (AMFs) triggers small-molecule release from thermally sensitive lipid vesicles with a 20 s latency. Coupled with the chemogenetic activation of engineered receptors, this technique permits the control of specific neurons with temporal and spatial precision. The delivery of chemomagnetic particles to the ventral tegmental area (VTA) allows the remote modulation of motivated behaviour in mice. Furthermore, this chemomagnetic approach activates endogenous circuits by enabling the regulated release of receptor ligands. Applied to an endogenous dopamine receptor D1 (DRD1) agonist in the nucleus accumbens (NAc), a brain area involved in mediating social interactions, chemomagnetic modulation increases sociability in mice. By offering a temporally precise control of specified ligand-receptor interactions in neurons, this approach may facilitate molecular neuroscience studies in behaving organisms.


Assuntos
Preparações de Ação Retardada/química , Sistemas de Liberação de Medicamentos , Nanopartículas de Magnetita/química , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Lipossomos/química , Campos Magnéticos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/fisiologia , Neurotransmissores/farmacologia , Ratos , Temperatura , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia
10.
Brain ; 142(9): 2705-2721, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363737

RESUMO

Temporal lobe epilepsy is associated with significant structural pathology in the hippocampus. In the dentate gyrus, the summative effect of these pathologies is massive hyperexcitability in the granule cells, generating both increased seizure susceptibility and cognitive deficits. To date, therapeutic approaches have failed to improve the cognitive symptoms in fully developed, chronic epilepsy. As the dentate's principal signalling population, the granule cells' aggregate excitability has the potential to provide a mechanistically-independent downstream target. We examined whether normalizing epilepsy-associated granule cell hyperexcitability-without correcting the underlying structural circuit disruptions-would constitute an effective therapeutic approach for cognitive dysfunction. In the systemic pilocarpine mouse model of temporal lobe epilepsy, the epileptic dentate gyrus excessively recruits granule cells in behavioural contexts, not just during seizure events, and these mice fail to perform on a dentate-mediated spatial discrimination task. Acutely reducing dorsal granule cell hyperactivity in chronically epileptic mice via either of two distinct inhibitory chemogenetic receptors rescued behavioural performance such that they responded comparably to wild type mice. Furthermore, recreating granule cell hyperexcitability in control mice via excitatory chemogenetic receptors, without altering normal circuit anatomy, recapitulated spatial memory deficits observed in epileptic mice. However, making the granule cells overly quiescent in both epileptic and control mice again disrupted behavioural performance. These bidirectional manipulations reveal that there is a permissive excitability window for granule cells that is necessary to support successful behavioural performance. Chemogenetic effects were specific to the targeted dorsal hippocampus, as hippocampal-independent and ventral hippocampal-dependent behaviours remained unaffected. Fos expression demonstrated that chemogenetics can modulate granule cell recruitment via behaviourally relevant inputs. Rather than driving cell activity deterministically or spontaneously, chemogenetic intervention merely modulates the behaviourally permissive activity window in which the circuit operates. We conclude that restoring appropriate principal cell tuning via circuit-based therapies, irrespective of the mechanisms generating the disease-related hyperactivity, is a promising translational approach.


Assuntos
Disfunção Cognitiva/metabolismo , Giro Denteado/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Rede Nervosa/metabolismo , Reconhecimento Psicológico/fisiologia , Animais , Disfunção Cognitiva/induzido quimicamente , Giro Denteado/química , Giro Denteado/efeitos dos fármacos , Epilepsia do Lobo Temporal/induzido quimicamente , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/química , Rede Nervosa/efeitos dos fármacos , Pilocarpina/toxicidade , Distribuição Aleatória , Reconhecimento Psicológico/efeitos dos fármacos
11.
Nat Commun ; 10(1): 3777, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439845

RESUMO

Investigation and modulation of neural circuits in vivo at the cellular level are very important for studying functional connectivity in a brain. Recently, neural probes with stimulation capabilities have been introduced, and they provided an opportunity for studying neural activities at a specific region in the brain using various stimuli. However, previous methods have a limitation in dissecting long-range neural circuits due to inherent limitations on their designs. Moreover, the large size of the previously reported probes induces more significant tissue damage. Herein, we present a multifunctional multi-shank MEMS neural probe that is monolithically integrated with an optical waveguide for optical stimulation, microfluidic channels for drug delivery, and microelectrode arrays for recording neural signals from different regions at the cellular level. In this work, we successfully demonstrated the functionality of our probe by confirming and modulating the functional connectivity between the hippocampal CA3 and CA1 regions in vivo.


Assuntos
Eletrofisiologia/instrumentação , Sistemas Microeletromecânicos , Rede Nervosa/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/fisiologia , Sistemas de Liberação de Medicamentos/instrumentação , Masculino , Camundongos , Camundongos Transgênicos , Microeletrodos , Técnicas Analíticas Microfluídicas/instrumentação , Rede Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Estimulação Luminosa/instrumentação
12.
PLoS Comput Biol ; 15(8): e1006938, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31469828

RESUMO

The mechanism(s) of action of most commonly used pharmacological blockers of voltage-gated ion channels are well understood; however, this knowledge is rarely considered when interpreting experimental data. Effects of blockade are often assumed to be equivalent, regardless of the mechanism of the blocker involved. Using computer simulations, we demonstrate that this assumption may not always be correct. We simulate the blockade of a persistent sodium current (INaP), proposed to underlie rhythm generation in pre-Bötzinger complex (pre-BötC) respiratory neurons, via two distinct pharmacological mechanisms: (1) pore obstruction mediated by tetrodotoxin and (2) altered inactivation dynamics mediated by riluzole. The reported effects of experimental application of tetrodotoxin and riluzole in respiratory circuits are diverse and seemingly contradictory and have led to considerable debate within the field as to the specific role of INaP in respiratory circuits. The results of our simulations match a wide array of experimental data spanning from the level of isolated pre-BötC neurons to the level of the intact respiratory network and also generate a series of experimentally testable predictions. Specifically, in this study we: (1) provide a mechanistic explanation for seemingly contradictory experimental results from in vitro studies of INaP block, (2) show that the effects of INaP block in in vitro preparations are not necessarily equivalent to those in more intact preparations, (3) demonstrate and explain why riluzole application may fail to effectively block INaP in the intact respiratory network, and (4) derive the prediction that effective block of INaP by low concentration tetrodotoxin will stop respiratory rhythm generation in the intact respiratory network. These simulations support a critical role for INaP in respiratory rhythmogenesis in vivo and illustrate the importance of considering mechanism when interpreting and simulating data relating to pharmacological blockade.


Assuntos
Modelos Neurológicos , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/inervação , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Biologia Computacional , Simulação por Computador , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Centro Respiratório/efeitos dos fármacos , Centro Respiratório/fisiologia , Sistema Respiratório/metabolismo , Riluzol/farmacologia , Canais de Sódio/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Tetrodotoxina/farmacologia
13.
Psychopharmacology (Berl) ; 236(12): 3541-3556, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31302721

RESUMO

RATIONALE: Ethanol-induced behavioural sensitization (EBS) does not occur uniformly in mice exposed to the sensitization paradigm. This suggests innate differential responses to ethanol (EtOH) in the reward circuitry of individual animals. OBJECTIVES: To better characterize the adaptive differences between low-sensitized (LS) and high-sensitized (HS) mice, we examined excitatory amino acid (EAA) and inhibitory amino acid (IAA) neurotransmitter levels in the nucleus accumbens (NAc) during EBS expression. METHODS: Male DBA/2J mice received five ethanol (EtOH) (2.2 g/kg) or saline injections, and locomotor activity (LMA) was assessed during EBS induction. EtOH mice were classified as LS or HS on the basis of final LMA scores. Following an EtOH challenge (1.8 g/kg) 2 weeks later, LMA was re-evaluated and in vivo microdialysis samples were collected from the NAc. RESULTS: Most differences in amino acid levels were observed within the first 20 min after EtOH challenge. LS mice exhibited similar glutamate levels compared with acutely treated (previously EtOH naïve) mice, and generally increased levels of the IAAs GABA, glycine, and taurine. By contrast, HS mice exhibited increased glutamate and attenuated levels of GABA, glycine, and taurine. CONCLUSION: These data suggest that the profile of amino acid neurotransmitters in the NAc of LS and HS mice significantly differs. Elucidating these adaptive differences contributes to our understanding of factors that confer susceptibility/resilience to alcohol use disorder.


Assuntos
Etanol/administração & dosagem , Rede Nervosa/metabolismo , Neurotransmissores/metabolismo , Núcleo Accumbens/metabolismo , Sinapses/metabolismo , Aminoácidos/metabolismo , Animais , Aminoácidos Excitatórios/metabolismo , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Microdiálise/métodos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Rede Nervosa/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Sinapses/efeitos dos fármacos
14.
Hum Brain Mapp ; 40(16): 4789-4800, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361073

RESUMO

Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, and -degenerative disease that affects the brain's neurophysiological functioning through brain atrophy, a reduced conduction velocity and decreased connectivity. Currently, little is known on how MS affects the fast temporal dynamics of activation and deactivation of the different large-scale, ongoing brain networks. In this study, we investigated whether these temporal dynamics are affected in MS patients and whether these changes are induced by the pathology or by the use of benzodiazepines (BZDs), an important symptomatic treatment that aims at reducing insomnia, spasticity and anxiety and reinforces the inhibitory effect of GABA. To this aim, we employed a novel method capable of detecting these fast dynamics in 90 MS patients and 46 healthy controls. We demonstrated a less dynamic frontal default mode network in male MS patients and a reduced activation of the same network in female MS patients, regardless of BZD usage. Additionally, BZDs strongly altered the brain's dynamics by increasing the time spent in the deactivating sensorimotor network and the activating occipital network. Furthermore, BZDs induced a decreased power in the theta band and an increased power in the beta band. The latter was strongly expressed in those states without activation of the sensorimotor network. In summary, we demonstrate gender-dependent changes to the brain dynamics in the frontal DMN and strong effects from BZDs. This study is the first to characterise the effect of multiple sclerosis and BZDs in vivo in a spatially, temporally and spectrally defined way.


Assuntos
Encéfalo/patologia , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Adulto , Benzodiazepinas/uso terapêutico , Ritmo beta/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Estudos de Coortes , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Imagem por Ressonância Magnética , Magnetoencefalografia , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Caracteres Sexuais , Ritmo Teta/efeitos dos fármacos
15.
Med Eng Phys ; 71: 91-97, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31311692

RESUMO

Microelectrode arrays (MEAs) allow the investigation of the pharmacological and toxicological effects of chemicals on cultured neuronal networks. Understanding the functional connections between neurons and the resulting neuronal networks is important for evaluating drugs that affect synaptic transmission. Therefore, we acutely treated a mature cultured neuronal network on MEAs with accumulating amounts of glutamate and recorded their altered electrophysiology. Subsequently, a cross-covariance analysis was applied to process the spiking activity in the network and to evaluate the connections between neurons. Finally, graph theory was used to assess the functional network properties under acute glutamate treatment. Our data demonstrated that glutamate increased the similarity, connectivity weight, density, and largest-component size of the functional network. In addition, the small-world network topology was altered after glutamate treatment. Our results indicate that the graph theory can advance our understanding of the pharmacological significance of neurotransmitters on neuronal networks.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Ácido Glutâmico/farmacologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Animais , Encéfalo/citologia , Feminino , Rede Nervosa/citologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
16.
Br J Anaesth ; 123(3): 298-308, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31277837

RESUMO

BACKGROUND: Emergence from sedation entails rapid increase in the levels of both awareness and wakefulness, the two axes of consciousness. Functional MRI (fMRI) studies of emergence from sedation often focus on the recovery period, with no description of the moment of emergence. We hypothesised that by focusing on the moment of emergence, novel insights, primarily about subcortical activity and increased wakefulness, will be gained. METHODS: We conducted a resting state fMRI analysis of 17 male subjects (20-40 yr old) gradually entering into and emerging from deep sedation (average computed propofol concentrations of 2.41 and 1.11 µg ml-1, respectively), using target-controlled infusion of propofol. RESULTS: Functional connectivity analysis revealed a robust spatiotemporal signature of return of consciousness, in which subcortical seeds showed transient positive correlations that rapidly turned negative shortly after emergence. Elements of this signature included four components of the ascending reticular activating system: the ventral tegmentum area, the locus coeruleus, median raphe, and the mammillary body. The involvement of the rostral dorsolateral pontine tegmentum, which is specifically impaired in comatose patients with pontine lesions, in emergence was previously unknown. CONCLUSIONS: Emergence from propofol sedation is characterised, and possibly driven, by a transient activation of brainstem loci. Some of these loci are known components of the ascending reticular activating system, whereas an additional locus was found that is also impaired in comatose patients.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Sedação Profunda/métodos , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Adulto , Período de Recuperação da Anestesia , Mapeamento Encefálico/métodos , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/fisiologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , Estado de Consciência/efeitos dos fármacos , Esquema de Medicação , Humanos , Hipnóticos e Sedativos/administração & dosagem , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/efeitos dos fármacos , Propofol/administração & dosagem , Adulto Jovem
17.
Transl Psychiatry ; 9(1): 172, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253763

RESUMO

Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.


Assuntos
Antidepressivos/farmacologia , Cérebro/efeitos dos fármacos , Conectoma , Depressão/tratamento farmacológico , Ketamina/farmacologia , Rede Nervosa/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Cérebro/diagnóstico por imagem , Cérebro/fisiopatologia , Modelos Animais de Doenças , Habenula/diagnóstico por imagem , Habenula/efeitos dos fármacos , Habenula/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Ratos , Ratos Sprague-Dawley , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologia
18.
PLoS One ; 14(6): e0218850, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237927

RESUMO

Cell patterning is becoming increasingly popular in neuroscience because it allows for the control in the location and connectivity of cells. A recently developed cell patterning technology uses patterns of an organic polymer, parylene-C, on a background of SiO2. When cells are cultured on the parylene-C/SiO2 substrate they conform to the underlying parylene-C geometry. Parylene-C is, however, just one member of a family of parylene polymers that have varying chemical and physical properties. In this work, we investigate whether two commercially available mainstream parylene derivatives, parylene-D, parylene-N and a more recent parylene derivative, parylene-HT to determine if they enable higher fidelity hNT astrocyte cell patterning compared to parylene-C. We demonstrate that all parylene derivatives are compatible with the existing laser fabrication method. We then demonstrate that parylene-HT, parylene-D and parylene-N are suitable for use as an hNT astrocyte cell attractive substrate and result in an equal quality of patterning compared to parylene-C. This work supports the use of alternative parylene derivatives for applications where their different physical and chemical properties are more suitable.


Assuntos
Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Polímeros/farmacologia , Xilenos/farmacologia , Materiais Biocompatíveis/química , Sinalização do Cálcio , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Teste de Materiais , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Polímeros/química , Dióxido de Silício , Propriedades de Superfície , Xilenos/química
19.
Neuroimage ; 200: 281-291, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247301

RESUMO

Classic serotonergic psychedelics are remarkable for their capacity to induce reversible alterations in consciousness of the self and the surroundings, mediated by agonism at serotonin 5-HT2A receptors. The subjective effects elicited by dissociative drugs acting as N-methyl-D-aspartate (NMDA) antagonists (e.g. ketamine and phencyclidine) overlap in certain domains with those of serotonergic psychedelics, suggesting some potential similarities in the brain activity patterns induced by both classes of drugs, despite different pharmacological mechanisms of action. We investigated source-localized magnetoencephalography recordings to determine the frequency-specific changes in oscillatory activity and long-range functional coupling that are common to two serotonergic compounds (lysergic acid diethylamide [LSD] and psilocybin) and the NMDA-antagonist ketamine. Administration of the three drugs resulted in widespread and broadband spectral power reductions. We established their similarity by using different pairs of compounds to train and subsequently evaluate multivariate machine learning classifiers. After applying the same methodology to functional connectivity values, we observed a pattern of occipital, parietal and frontal decreases in the low alpha and theta bands that were specific to LSD and psilocybin, as well as decreases in the low beta band common to the three drugs. Our results represent a first effort in the direction of quantifying the similarity of large-scale brain activity patterns induced by drugs of different mechanism of action, confirming the link between changes in theta and alpha oscillations and 5-HT2A agonism, while also revealing the decoupling of activity in the beta band as an effect shared between NMDA antagonists and 5-HT2A agonists. We discuss how these frequency-specific convergences and divergences in the power and functional connectivity of brain oscillations might relate to the overlapping subjective effects of serotonergic psychedelics and glutamatergic dissociative compounds.


Assuntos
Ondas Encefálicas/efeitos dos fármacos , Conectoma , Antagonistas de Aminoácidos Excitatórios/farmacologia , Alucinógenos/farmacologia , Ketamina/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Aprendizado de Máquina , Rede Nervosa/efeitos dos fármacos , Psilocibina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Adulto , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Alucinógenos/administração & dosagem , Humanos , Ketamina/administração & dosagem , Dietilamida do Ácido Lisérgico/administração & dosagem , Magnetoencefalografia , Psilocibina/administração & dosagem , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem
20.
Biosens Bioelectron ; 140: 111329, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163396

RESUMO

Lab-on-chip platforms, such as microfluidic chips and micro-electrode arrays (MEAs) are powerful tools that allow us to manipulate and study neurons in vitro. Microfluidic chips provide a controlled extracellular environment that structures neural networks and facilitates isolation and manipulation at a sub-cellular level. Furthermore, MEAs enable measurement of extracellular electrophysiological activity from single neurons to entire networks. Here, we demonstrate the design, fabrication and application of a 3-nodal microfluidic chip integrated with MEAs as a versatile study platform for neurobiology and pathophysiology. In this work, we evaluate the use of the microfluidic chip to structure a neural network into three separate nodes, interconnected through tunnels that isolate and guide axons into a channel, thus facilitating synaptic contacts between neurons originating from opposite nodes. Furthermore, we demonstrate the utility of the MEA for monitoring developing activity and intra-/inter nodal connectivity of the structured neural network. Finally, we demonstrate the versatility of the platform in two separate experiments. First, we demonstrate the ability to measure intra- and inter-nodal dynamic responses to a fluidically isolated chemical stimulation. Then, we demonstrate the feature of the microfluidic chip enabling the disruption of functional connectivity between nodes and examination of the immediate activity response of the neural network. The platform enables in vitro modelling of neural networks to study their functional connectomes in the context of neurodegenerative disease and CNS trauma, including spinal cord injury.


Assuntos
Técnicas Biossensoriais/instrumentação , Dispositivos Lab-On-A-Chip , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Axotomia , Linhagem Celular , Desenho de Equipamento , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
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